2004 Pilot Study Grants

Funding from The Parkinson Alliance helped to finance the following Parkinson's research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.

1. Characterisation of the functional anatomy of neurons of the pedunculopontine nucleus: establishing a rationale for therapeutic intervention in Parkinson's Disease

The classic model of the neuroanatomy of Parkinson’s disease is the direct/indirect pathways model of neurotransmission, first so named by Drs. John B. Penney and Anne B. Young, then further elucidated by Dr. Mahlon DeLong. Chemical activations of each pathway have either inhibitory (calming) or disinhibitory (excitatory) effects on the brain structures located therein. Surgical procedures that relieve disease symptoms are aimed at several of these structures as well. For some time, basic scientists have looked at additional structures within the basal ganglia area, e.g., the pedunculopontine tegmental nucleus (PPN), since some PD symptoms do not respond as well as do others to the usual medications. Dr. J. Paul Bolam and his Oxford (U.K.) colleagues will use their grant to examine the varied neurons of the PPN in rats, hoping to be able to correlate the activities of these cells with their impacts on those neurons in the basal ganglia known to be altered in animal models of parkinsonism, and thus better determine sites for potential therapy for human patients.

Synphilin-1 is a protein found in neurons on the presynaptic or donating side of the synapse that is known to interact with another protein, alpha-synuclein, and both substances are found in Lewy bodies, the hallmarks of PD. Dr. Simone Engelender and her co-workers at Technion (Haifa, Israel) will use their funding to try to delineate the former protein’s role (when degraded or mutated) in the formation of Lewy bodies and possibly in the mechanisms that lead to dopaminergic neurons dying off and producing symptoms of PD. They hope to create a neuronal cell culture model of Lewy bodies that could prove helpful in screening potential antiparkinson medications.

3. Phase II Clinical Trial of Ipratropium Bromide Spray as a Treatment for Sialorrhea in Patients with Parkinson's Disease

Instead of creating totally new drugs, a current approach is to try to use approved drugs for additional purposes. Ipratropium bromide spray is an anticholinergic drug used in patients with asthma and pulmonary disorders. Like anticholinergic drugs (such as trihexyphenidyl or benztropine) used by PD patients, it decreases saliva production. Many PD patients report sialorrhea (excessive drooling); however, the problem is not that but loss of automatic swallowing. Dr. Susan H. Fox (Toronto Western Hospital) and her group will recruit patients for a Phase II clinical trial (randomized, double-blinded and placebo-controlled) of the spray in the hope that the resultant safety and tolerability data will provide sufficient reason for a larger Phase III study. One would also hope that the manufacturer will financially support such a study if the Canadian group’s data are positive.

4. Nanoparticulate delivery of functional protein into neuronal cells

Dr. Julia M. George
University of Illinois at Urbana-Champaign, Urbana, IL

Dr. Daewoo Lee (Ohio University) will use transgenic fruit flies that express human alpha-synuclein, a protein found in familial parkinsonian brains both in mutated forms and in higher amounts of the non-mutated form, in an attempt to better describe the role of this protein in classic PD. He hopes to explain how @-synuclein interacts with dopamine, with the dopamine transporter and with tyrosine hydroxylase, the enzyme that facilitates the transformation of levodopa to dopamine.

6. Reduction of L-DOPA-induced dyskinesias by retinoid agonists: a new way to improve Parkinson's disease treatment

Dr. Daniel Levesque
Laval University, Quebec, Canada

Retinoic acids (RA) regulate certain target genes’ expression and their receptor sites are thought to be involved in the dopaminergic (DA) system. Retinoic ligands (allied substances) can modify levodopa-induced side effects in mouse models of parkinsonism and a team at Laval University (Quebec City) is being funded to use retinoic acid agonists to try to reduce dyskinesias in an MPTP-primate model of parkinsonism. Since these LIDs are easier to prevent than reverse, the team, led by Dr. Daniel Levesque in the department of Dr. Paul J. Bedard, will also administer the agonist, docosahexaenoic acid (DHA) to similar animals never before exposed to levodopa. Should such compounds prevent these effects in human patients, it would be a major improvement in symptomatic treatment.

Dr. Gil Levkowitz and his Weizmann Institute colleagues (Israel) will use their funds to study zebrafish as an alternate vertebrate model in an attempt to identify factors that control proliferation, survival and behavior of implanted neuronal cells. Their goal is to determine which gene(s) might affect development of embryonic cells that, when implanted, have effects on the host neurons. Understanding the molecules that instruct these cells to survive and blend into the host brain may provide better insight into both the benefits derived and the dyskinesias that proved so disabling in some transplanted patients that additional surgical procedures were required.

What causes alpha-synuclein to aggregate and form fibrils (small fibers found in cell bodies and axons of neurons) when genetically mutated or found in increased amounts? This protein is involved in a number of neurodegenerative disorders, termed “synucleinopathies” by Dr. John Q. Trojanowski at Penn. Dr. Vasanthy Narayanaswami and her post-docs at Children’s Hospital (Oakland, California) plan to use their funding on spectroscopic analyses of @-synuclein in an attempt to better understand the molecular basis of its aggregates and fibrils, an essential step, they say, to devising actual treatments for this group of disorders that includes PD and Alzheimer’s disease.

9. Role of INF-r in Parkinson's

Dr. David S. Park
University of Gttawa, Ottawa, Ontario, Canada

Neuronal inflammation is a topic of much research these days, and is thought to be a possible cause of dopaminergic cell loss. If compounds that cause inflammation of microglia (neuronal support cells) are part of the cascade pathway to neuronal death, it may be possible to inhibit these compounds and provide neuroprotection. Dr. David S. Park (University of Ottawa) will use the MPTP-mouse model of parkinsonism to try to determine if a specific inflammatory, IFN-gamma, already found to be elevated in sera of PD patients, acts with the neurotoxin MPTP to induce further cell death. Learning whether IFN action is on microglia alone, or on neurons as well, would suggest additional experiments that might pin down where intervention in the cascade might be possible.

Among the hereditary or familial parkinsonisms that have been identified are those affected by the DJ-1 gene and others by the parkin gene. However, it is not clear what effect either of these genes, wild-type (normal) or mutated, has on classic Parkinson’s disease, if any. Dr. Emmanuel N. Pothos of Tufts University will use transgenic mouse strains of each in an attempt to determine such effects, thus validating one strain or the other, or both, as valid animal models of classic disease. Animal models of parkinsonisms exist, to be sure, and are useful in testing compounds and surgical procedures prior to use in human patients. None, however, completely mimics the human disease as yet. (N.B: None is a singular noun and, as such, requires a singular verb, unlike as seen in the New York Times of late.)

Two proteins, when mutated, DJ-1 and alpha-synuclein have been linked to early-onset parkinsonism in families. Dr. Jean-Christophe Rochet and his Purdue University colleagues will use their award to try to tell us, using mesencephalic cultures, what effect losses of these genes’ functions might have on the losses of dopaminergic neurons in their specific disorders. They will also seek answers regarding possible interplays between genetic and environmental factors as causes of these diseases. More definitive data might lead to therapeutic approaches such as drugs that upregulate one of the genes or even mimic the wild-type forms’ neuroprotective abilities.

RNA interference (RNAi) is a process of silencing genes that is proving quite specific to the gene in question. This process is being used increasingly in basic research studies in numerous neurodegenerative disorders such as frontotemporal dementia. A group in Dr. Martha C. Bohn’s laboratories at Chicago’s Northwestern University will use an MPTP-rat model of parkinsonism in their funded study. Led by Dr. Mohan K. Sapru, they will create a lentiviral vector-based system for the silencing of both wild-type and mutant forms of human alpha-synuclein, asking if such muting could be developed into a therapeutic approach for classic PD. Alpha-synuclein has been shown to be present in postmortem PD brains but it is not clear whether it is a cause of or effect of the disorder.

13. Production of Alpha-Synuclein Fragments and Pathogenesis in Parkinson's Disease

Dr. Philip J. Thomas
U.T. Southwestern Medical Center, Dallas, TX

Proteomics has been defined as the study of the manner in which proteins, expressed by genes, interact within cells and the study of which is aimed at determining differences in the actions of proteins between diseased and healthy cells. Drs. Philip J. Thomas and Chang-Wei Liu (University of Texas in Dallas) will use transgenic mice to plot a proposed pathway of neurodegeneration and then try to learn how alpha-synuclein is metabolized as well as the chemical properties of the protein (and fragments thereof). Knowledge of how and why @-synuclein is toxic to cells (cytotoxicity) could suggest preventive forms of therapy for human PD patients (the protein is found in aggregates in postmortem PD brains).

14. Molecular investigation of two FGF20 polymorphisms that are strongly associated with increased risk of Parkinson' disease

Dr. Joelle Van der Walt
Duke University Medical Center, Durham, NC

In genetic disorders, many genes have one normal version (wild-type), while other genes exhibit polymorphism (literally many forms), describing the information at particular loci on the gene. Called SNPs (and pronounced snips), these can now be typed and examined in the genes of members of a specific family in order to better understand the family’s disorder. The grant is supporting Dr. Joelle van der Walt (Duke University) in her study of FGF20, a growth factor that seems to be required for the health of nigral dopaminergic neurons, though how it protects is not yet known. She plans to examine numerous SNPs taken from individuals in a large parkinsonian family to learn if and how these might affect FGF20 expression, and thus learn more about the degeneration of cells seen in PD. Her hope is that her results would provide information leading to protective therapy.

15. a-Synuclein and the Proteasome

Dr. Konstantinos Vekrellis
Foundation of Biomedical Research of the Academy of Athens, Athens, Greece

The ubiquitin-proteasomal system is thought to have multiple roles in the brain, e.g., in regulating growth and cell differentiation, and “quality-control” of the disposal of misfolded or damaged proteins to prevent potentially toxic aggregates. When it goes awry through numerous mechanisms, such aggregates build up, causing or adding to existing problems. Grant funds are going to Dr. Konstantinos Vekrellis (Academy of Athens, Greece) to explore, using cell cultures, the relationship between the aberrant alpha-synuclein found in brains of familial parkinsonians and this degradation system. The hope is to determine common mechanisms of cell dysfunction between parkinsonism and classic PD, leading to clues to the pathophysiology of the sporadic disorder that is so much more commonly seen.

Nitric oxide (NO) is thought by many to play a role in facilitating dopamine (DA) transmission, in enhancing the release of exogenous (added) levodopa and in promoting neuronal plasticity, thus compounds that increase NO signaling may prove to benefit patients. Dr. Anthony R. West (Chicago Medical School) will use his grant to test, in rats, the possible mechanisms of increasing NO signaling since it has already been found that inhibiting this substance in rodents decreases natural motor activity as well as those movements stimulated by dopamine agonists and NMDA-receptor antagonists (drugs already approved for symptomatic therapy in PD).

17. Development of Novel Therapeutics Targeting DJ-1 for Parkinson's Disease

Dr. Jin Xu
Caritas St. Elizabeth's Medical Center, Boston MA

The mutated DJ-1 gene has now been implicated in an autosomal recessive form of parkinsonism, but it is not yet known what the natural functions of this gene in neuronal cells might be. Some believe that the gene protects against toxicity caused by alpha-synuclein and/or cell death (apoptosis) caused by oxidative stress. Dr. Jin Wu and his colleagues will use their grant in an attempt to create screening assays to use on already available drugs that can activate this gene’s expression in neurons. If the gene proves to be an antioxidant, and can identify drugs that activate it, their data would be very useful in developing drugs that are aimed at protecting against neurodegeneration.

18. Iron Regulatory Genes as Modifiers of Susceptibility and Age of Onset in Parkinson's Disease

Dr. Cyrus Zabetian
VA Puget Sound Health Care System, Seattle, WA

It has long been known that neurons are vulnerable to oxidative stress (the breakdown of compounds that produces reactive oxygen species {ROS} that do damage if not scavenged out). Iron and its metabolites (byproducts) are considered by many groups to play a role in Parkinson’s disease, whether as cause, as an early pathogen or as an additive to impairment. Dr. Cyrus Zabetian (VA, Puget Sound, Seattle) and his group will use their funds to genetically type a thousand PD patients and an equal number of control subjects in order to look for polymorphisms of two iron regulatory genes, HFE and TF, as well as control SNPs to allow for population differences among the testees. A better understanding of the role of iron could lead to potential neuroprotective drugs, especially if they can be “targeted” to those individuals who prove susceptible via genetic typing.